JP2020510472A - Quantum information processing system - Google Patents

Abstract

Provided is a cardiovascular graft with greatly reduced thrombogenicity. The cardiovascular graft is an electrospun nonwoven mesh made from a supramolecular polymer containing large diameter fibers. The cardiovascular graft is realized as a vascular graft into the human body and allows repeated venous access for vascular bypass / reconstruction, or dialysis treatment, and treatment of other disorders of small diameter vessels. [Selection diagram] Fig. 6

Description

  The present invention relates to electrospun coatings, implants or materials for inhibiting the effect of thrombus formation.

  Vascular diseases involving blood vessels with a tube diameter of 6 mm or less account for the majority of disease cases requiring clinical intervention. In many of these cases, the preferred intervention is vascular reconstruction or bypass surgery utilizing autologous or synthetic vascular grafts taken from another location in the patient. Such synthetic implants are available in a variety of sizes and configurations, and are generally woven or dendritic assemblies of poly (tetrafluoroethylene) (PTFE) or poly (ether terephthalate) (PET). ) Has a small set of medical polymers.

  The predominant form of synthetic vascular graft failure observed in the clinical setting is a progressive intimal hyperplasia of the venous (outflow) anastomosis leading to graft blood flow and reduction and thrombosis. This is due to the foreign body thrombogenicity of the graft material in contact with the circulating blood, as well as the perturbation of flow due to the mismatch between the graft and the natural vessel, and the mechanical properties (eg, conformability) of the graft material and natural tissue It is believed to be caused by: However, the exact mechanism of thrombosis remains a major focus of research in this area today.

  Hemostasis involves a myriad of biological processes that stop bleeding from damaged tissue or blood vessels. The main mechanism of hemostasis is the activation and adhesion of circulating platelets, also known as platelets. Within seconds of tissue damage, the released proteins “activate” the platelets, develop an adherent structure on their surface, and begin to form “plugs” that bind to the site of injury and prevent further blood loss. In addition, activated platelets emit additional chemical signals to recruit and activate further circulating platelets in a cascade effect, and these platelets bind either to the site of injury or other activated platelets.

  Intravascular thrombi result from pathological disorders of the hemostatic process. In many cases, platelets are activated, adhered, and aggregated in blood vessels due to turbulence, foreign body interaction with circulating platelets, release of signaling proteins from damaged vessel walls, and the like. When these platelets are activated, the circulating platelets that attach to the further growing thrombus are further activated, resulting in occlusion of the blood vessels, restricting or completely stopping blood flow. These conditions are exacerbated in low volume flow vessels, typically less than 600 mL / min. This occurs because circulating platelets that remain for long periods of time near growing thrombi, and reduced shear stress on adherent platelets due to reduced flow reduce the likelihood of activated platelets being removed. .

US Patent Application Publication No. 2010/0280594 International Publication No. WO 2014/185779

Dobrovolskaia et al, 2012 Nanoparticle size and surface charge determine effects of PAMAM dendrimers on human platelets in vitro. Molecular pharmaceutics. 2012; 9 (3): 382-393.doi: 10.1021 / mp200463e

  The present invention advances the art by providing vascular grafts with greatly reduced thrombogenicity.

  Cardiovascular grafts for reducing thrombogenic effects are provided for applications such as coronary artery bypass grafts or arteriovenous grafts for dialysis access. Cardiovascular grafts include a tubular structure with an inner wall made of a fibrous network of supramolecular compounds having a hard block covalently bonded to a soft block. The hard block comprises a 2-ureido-4 [1H] -pyrimidinone (UPy) compound. The hard block may comprise a chain extension in the range of 1 to 5, more preferably 1.5 to 3, relative to the UPy compound. The soft block comprises a biodegradable polyester, polyurethane, polycarbonate, poly (ortho) ester, polyphosphoester, polyanhydride, polyphosphazene, polyhydroxyalkanoate, polyvinyl alcohol, polypropylene fumarate, or any combination thereof. Including. The molecular weight range of the soft block is 500-3000 Da.

  The fibrous network is a bioabsorbable electrospun nonwoven fiber network having fibers having an average fiber diameter of 1 to 10 μm. The tubular structure has an inner diameter of 2-8 mm and a wall thickness of 200-900 μm.

  In another variation of the embodiment, the inner wall has pores, the average porosity of the inner wall is 50-80%, and the average pore diameter of the pores is 5-8 μm.

  In still another variant of the embodiment, the inner diameter of the tubular structure is 3-6 mm and the wall thickness of the tubular structure is 200-800 μm.

  In yet another variation of the above embodiment, the inner diameter of the tubular structure is 4-8 mm and the wall thickness of the tubular structure is 300-900 μm.

  In still another variation of the above embodiment, the inner diameter of the tubular structure is no more than 5 mm.

  In still another variation of the above embodiment, the fibers have an average fiber diameter of 4-8 μm.

  In yet another variation of the above embodiment, the fibers have an average fiber diameter of 4-6 μm.

  In yet another variation of the above embodiment, the inner wall is hydrophobic and the inner wall has a water contact angle of 110-140 degrees.

  In yet another variation of the above embodiment, the tubular structure has an outer wall reinforced with a braided structure, polymer strand, compound, or a combination thereof to provide resistance to prevent collapse of the cardiovascular graft. .

  In yet another variation of the above embodiment, the cardiovascular graft may further include an αIIbβ3 inhibitor.

  In yet another variation of the above embodiment, implantation of the cardiovascular graft may be performed in combination with administration of an αIIbβ3 inhibitor.

1A-1C are SEM images of platelet adhesion and activation on supramolecular polymer (SP) micron (μm) and submicron electrospun fibers according to an exemplary embodiment of the invention compared to a PTFE nonwoven fabric (magnification 10 ×). 2,000 times). FIG. 1A shows a high magnification image of platelet adhesion and spread on SP electrospun fibers having an average diameter of 4 to 6 μm. FIG. 1B shows a high magnification image of platelet adhesion and spread of SP electrospun fibers having an average diameter of less than 1 μm. FIG. 1C shows a high magnification image of platelet adhesion and spread on nonwoven PTFE fibers having an average diameter of less than 1 μm. 2A-2C show platelets spreading on SP micron fibers and sub-micron fibers according to an exemplary embodiment of the present invention, as compared to a PTFE nonwoven. FIG. 2A shows a low magnification image of platelet diffusion behavior with SP electrospun fibers having an average diameter of 4-6 μm. FIG. 2B shows a low magnification image of platelet diffusion behavior with SP electrospun fibers having an average diameter of less than 1 μm. FIG. 2C shows a low magnification image of the platelet diffusion behavior of nonwoven PTFE fibers having an average diameter of less than 1 μm. 3A-3C illustrate a method for analyzing the surface porosity of a test material after blood perfusion, according to an exemplary embodiment of the present invention. Each image is (FIG. 3A): the original SEM image, (FIG. 3B): a contrast image cut out and enhanced from FIG. 3A, (FIG. 3C): a binary image generated from FIG. 3B, and ImageJ ™. Automatic thresholding was performed by software to give a total porosity of 27.35% as absolute black / white pixels from FIG. 3C. FIG. 4 shows the decrease in porosity observed under SEM for test material after blood perfusion by platelet aggregation / diffusion as a percentage of initial porosity, according to an exemplary embodiment of the present invention. . FIG. 5 shows the detection of activated αIIbβ3 in perfused blood from a test surface, according to an exemplary embodiment of the present invention. FIG. 6 shows SEM images at multiple magnifications of platelet adhesion to electrospun SP and PTFE nonwoven materials with and without abciximab, according to an exemplary embodiment of the present invention. Is shown. 7A-7C show animals receiving heparin (FIG. 7A), animals receiving heparin and Aspirin ™ (FIG. 7B), and heparin, Aspirin ™ and Plavix, according to exemplary embodiments of the present invention. FIG. 7 shows an enlarged SEM image (250 ×) of a sample obtained by transplantation into an animal (FIG. 7C) to which (trademark) was administered. FIG. 8A shows an angiogram of a 6 mm carotid intervening graft after 6 months of implantation, with arrows indicating distal (upper) and proximal (lower) anastomosis, according to an exemplary embodiment of the present invention. Is shown. FIG. 8B shows an angiogram of a 6 mm carotid intervening graft after 6 months of implantation, with arrows indicating distal (upper) and proximal (lower) anastomosis, according to an exemplary embodiment of the invention. Show. FIG. 8C shows an angiogram of a 7 mm carotid intervening graft after 6 months of implantation, with arrows indicating distal (upper) and proximal (lower) anastomosis, according to an exemplary embodiment of the invention. Show. FIG. 9 shows the inner diameter of the graft measured immediately before distal anastomosis for 6 mm and 7 mm carotid intervened grafts implanted for 36 weeks, according to an exemplary embodiment of the present invention. FIG. 10 shows data of increasing injection volume versus pore size in a small diameter implant according to an exemplary embodiment of the present invention, showing that the majority of the pores have a pore size in the range of 5-10 μm. The average pore size of the cardiovascular graft according to the present invention is different from that observed, ie, desired, at the pulmonary valve. FIG. 11 illustrates that alignment of fibers according to an exemplary embodiment can increase fatigue resistance, which can be measured by an accelerated wear tester (AWT) of a supramolecular polymer valve under aortic conditions according to ISO 5840. ) Is expressed as the number of cycles until failure.

  The present invention relates to cardiovascular grafts with greatly reduced thrombogenicity by having an electrospun mesh made from a supramolecular polymer (SP). Preferably, the vascular graft is a non-woven mesh and / or large diameter fibers. The invention also relates to a method for producing such an implant via electrospinning. The present invention further relates to the implantation of a vascular graft into a human body that allows repeated venous access for vascular bypass / reconstruction, or dialysis procedures, and treatment of other disorders of small vessels.

  For the design of cardiovascular grafts, we have demonstrated and described herein unexpected platelet behavior in vascular grafts made from SP, as defined below. In contrast to widely available "biocompatible" materials such as PTFE, platelet activation and adhesion was observed without significant spreading, aggregation, or filopodia formation. These results demonstrate that it is an ideal material for small diameter implants where thrombus and / or stenosis is a significant problem. Further, the SP material employed is bioabsorbable, allowing tissue infiltration and regrowth. This greatly reduces the risk of continued inflammatory response leading to long-term remodeling, neointima formation, and stenosis of blood vessels.

[ Definition of cardiovascular graft to suppress thrombus formation ]
Cardiovascular grafts for reducing the thrombogenic effect are defined by a tubular structure with an inner wall made of a fibrous network of supramolecular compounds having a hard block covalently bonded to a soft block. The hard block contains a 2-ureido-4 [1H] -pyrimidinone (UPy) compound. The fibrous network is a bioabsorbable electrospun nonwoven fiber network having fibers having an average fiber diameter of 1 to 10 μm. The tubular structure has an inner diameter of 2-8 mm and a wall thickness of 200-900 μm.

Variations of a cardiovascular graft are defined by the following structural aspects, individually or, where applicable, in any combination.
An inner wall having a thickness of at least 20 μm and an average pore diameter of 5 to 10 μm.
An inner wall having pores having an average pore diameter of 5 to 8 μm and an average porosity of 50 to 80%.
A tubular structure with an inner diameter of 3-6 mm and a wall thickness of 200-800 μm.
A tubular structure with an inner diameter of 3-8 mm and a wall thickness of 300-900 μm.
-A tubular structure having an inner diameter of 5 mm or less.
-Fibers with an average fiber diameter of 4-8 [mu] m or 4-6 [mu] m.
A soft block containing biodegradable polyester, polyurethane, polycarbonate, poly (ortho) ester, polyphosphoester, polyanhydride, polyphosphazene, polyhydroxyalkanoate, polyvinyl alcohol, polypropylene fumarate, or any combination thereof .
-Soft block with a molecular weight of 500-3000 Da.
A hard block comprising a chain extension in the range of 1 to 5, more preferably 1.5 to 3, relative to the UPy compound.
-The inner wall of the graft is hydrophobic, and the water contact angle of the inner wall is 110 to 140 degrees.
-The cardiovascular graft is a coronary artery bypass graft.
The tubular structure has an outer wall reinforced with braided structures, polymer strands, compounds, or a combination thereof to provide resistance to prevent cardiovascular graft collapse.
The cardiovascular graft further comprises an αIIbβ3 inhibitor, which further reduces the thrombogenic effect.
The cardiovascular graft is provided in combination with the administration of an αIIbβ3 inhibitor, which further reduces the thrombogenic effect.

  Supramolecular polymers (SPs) referred to herein include ureido-pyrimidinone (UPy) quadruple hydrogen bonding motifs and polymer backbones such as biodegradable polyesters, polyurethanes, polycarbonates, poly (orthoesters), polyphosphoesters , Polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, polyvinyl alcohols, and polypropylene fumarate. Examples of polyesters include polycaprolactone, poly (L-lactide), poly (DL-lactide), poly (valerolactone), polyglycolide, polydioxanone, and copolyesters thereof. Examples of polycarbonate include poly (trimethylene carbonate), poly (dimethyltrimethylene carbonate), and poly (hexamethylene carbonate).

  The same reduction in platelet adhesion can occur with alternative non-supramolecular polymers when the material is carefully selected and the material is treated to ensure the required surface properties. These polymers include biodegradable or non-biodegradable polyesters, polyurethanes, polycarbonates, poly (orthoesters), polyphosphoesters, polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, polyvinyl alcohol, polypropylene fumarate, etc. Is mentioned. Examples of polyesters include polycaprolactone, poly (L-lactide), poly (DL-lactide), poly (valerolactone), polyglycolide, polydioxanone, and copolyesters thereof. Examples of polycarbonate include poly (trimethylene carbonate), poly (dimethyltrimethylene carbonate), poly (hexamethylene carbonate) and the like.

  In addition, the morphology of the luminal surface of the implant plays an important role in the thrombogenic properties. Experiments performed in vitro using human blood have revealed that the fiber diameter of the nonwoven mesh is important and that large diameter fibers of 4-6 μm are preferred over small diameter fibers.

[ Platelet aggregation on scaffolds made of supramolecular polymers ]
Samples of electrospun SP material of various surface morphologies were coated on indium tin oxide (ITO) coated PET sheets. These samples were subjected to perfusion through a constant shear rate flow cell to human blood containing 3.2% citrate to inhibit thrombin activation so that the platelet behavior could be specifically investigated. did. Thirty minutes after perfusion, the flow cell was removed, the surface of the material was fixed using ethanol dehydration, and characterized by scanning electron microscopy (SEM). Negative controls were performed on PET-ITO sheets without sample coating and did not show significant platelet adhesion. Positive controls were performed on PET-ITO coated with collagen and showed significant platelet cluster formation. All experiments were performed in triplicate on multiple healthy blood donors.

  The electrospun SP mesh showed a significant reduction in platelet activity as compared to a commercially available PTFE nonwoven material. This effect was most evident with larger diameter fibers, but with a similar morphology to the PTFE nonwoven fabric, a reduction in spread was also evident with submicron fibers. SEM images of platelet adhesion to SP fibers and non-woven PTFE are shown at high magnification (10,000 times). Although platelet adhesion and activation to the fibers are clearly observed, the aggregation and diffusion of platelets is significantly reduced compared to the PTFE nonwoven fabric. Low magnification (1,000 ×) SEM images of all substrates are also shown, showing reduced platelet spread and aggregation over a larger area.

  UPy-based electrospun fibers exhibit reduced platelet diffusion and aggregation in human blood as compared to similar forms of commercially available biocompatible materials. The observed platelet behavior is unusual and is very compatible with bioabsorbable devices to achieve tissue remodeling. The presence of the activated platelet coating triggers a subsequent remodeling phase and re-epithelialization. However, the presence of an active platelet layer often results in a severe thrombogenic response, resulting in rapid occlusion of small diameter conduits composed of synthetic materials. Thus, this demonstrated platelet response represents an ideal situation for the formation of neoplasia on a bioabsorbable substrate, which was theorized to result in a completely non-thrombogenic biological surface. ing. In addition, the nature of the supramolecular chemistry provides some flexibility in the mechanical properties of the synthetic polymer, which increases the tunability of the device properties and further improves the blood response.

  Quantification of the surface coverage of the blood product on the test material was based on an analysis of the decrease in total porosity of the surface observed by SEM. The analysis was performed using ImageJ ™ software, a summary of which steps are described in FIGS. 3A-3C. Briefly, SEM images are created by cropping and contrast enhancement and conversion to a binary image (an image containing only black or white pixels). The binary image is analyzed using ImageJ ™ 's “threshold” function, which counts the total number of black pixels in the image. This process is performed on three characteristic SEM images of the sample surface prior to blood perfusion, and the changes in porosity and SEM images of the surface after blood perfusion are reported. FIG. 4 shows the reduction in porosity by surface coating with blood products in all material samples after perfusion onto the surface.

  In addition to blood flow experiments using thrombin inactivated human blood, static experiments were performed using whole blood. In these experiments, blood from a healthy donor was placed in a 96-well plate with a sample of the test material. After incubating the sample chamber in a shaking incubator at 37 ° C. for 20 minutes, blood was removed with a pipette and characterized by flow cytometry.

  These experiments show an unexpected 50% decrease in cell adhesion for the glycoprotein αIIbβ3 in blood incubated with the electrospun SP material as compared to effluent blood samples from nonwoven PTFE, and No decrease in the adhesion of another adhesive glycoprotein, P-selectin, was observed (FIG. 5).

[ Very effective inhibition of platelet adhesion of supramolecular polymers to fibers by inactivation of integrin αIIbβ3 ]
Based on the results from cytometry of whole blood experiments on various samples, the assumption was made that platelet activation and adhesion by electrospun SP fibers was strongly and specifically dependent on integrin αIIbβ3.

  To confirm the mechanism of adhesion, abciximab (ReoPro ™), an inhibitor of αIIbβ3, was added to healthy blood with 10 μg / ml citrate, a clinically relevant dose. Subsequently, using a controlled shear rate flow cell for 30 minutes, blood was perfused into a sample of electrospun nonwoven SP material and a sample of nonwoven PTFE having a fiber diameter of 4-6 μm. After flow, the samples were fixed and imaged using a scanning electron microscope so that platelet adhesion could be directly visualized. Addition of abciximab (ReoPro ™) significantly reduced platelet adhesion as compared to controls (FIG. 6). Furthermore, the effect was greatly exaggerated compared to the case of the PTFE nonwoven fiber material. The ability to use a single clinically available drug (ReoPro ™) at physiologically relevant doses to provide near complete inhibition of platelet adhesion to synthetic polymer material (XP) is obtained. This is a new discovery that can be applied to various blood contact applications.

  The number of platelets absorbed into the test material counted from the SEM image above was reduced by 97% in the SP electrospun material after addition of abciximab compared to 78% for the PTFE nonwoven fabric (236 to 51). (226 to 6). Based on the apparent specific efficacy of abciximab as a platelet absorption inhibitor of electrospun SP material, together with the above data of the in vitro thrombus formation test for glycoprotein IIb / IIIa levels after perfusion, glycoprotein IIb / IIIa It has been proposed that any antiplatelet chemotherapeutic agent that has a mechanism of action that targets the inhibition of ATP exerts similarly exaggerated effects on SP electrospun materials. The mechanism of this extended effect is not clear, but is hypothesized to be caused by differences in apparent surface charge density and / or the associated hydrophobicity of the SP electrospun material. It is known that surface charge density, or charge per unit area of a material surface, affects protein binding. This effect occurs because the charge distribution within these proteins results in attracting / repelling effects from different / likely charged surfaces, respectively. In addition, materials that exhibit a significant degree of surface roughness have the effect of increasing the total charge density in micro-scale protrusions from flat surfaces and in the curvature region of nano-scale roughness and protrusions on these surfaces. May be further exaggerated or exacerbated. Such effects of surface charge on platelet activation have been established in the literature on synthetic polymers of dendrites, Dobrovolskaya et al., 2010.

  Furthermore, it is known to include chemotherapeutic agents such as abciximab in electrospun fibers and polymer coatings (Patent Document 1). Due to the apparent specific interaction between the SP electrospun material and the glycoprotein IIb / IIIa inhibitors, especially abciximab, a very effective antithrombotic effect can be achieved by this method. The combination of a bioabsorbable electrospun supramolecular construct with abciximab or other compounds targeting glycoprotein IIb / IIIa inhibition has heretofore been impossible in applications such as coronary artery bypass grafting. It is expected to be particularly effective as it may allow the body to regenerate its own tissue. It is contemplated that other methods of including such chemotherapeutic agents are possible as well, including, but not limited to, covalently bound or absorbed on fiber surfaces, carriers coated on nonwoven surfaces. Inclusion in the material also includes incorporation into the electrospun fiber material. Yet another possible way is to administer the chemotherapeutic agent orally, intravenously or otherwise. This administration can be performed before, during, or after the implantation of the cardiovascular graft.

[ Role of platelets in thrombus occlusion of small diameter grafts of electrospun supramolecular polymer (SP) material in large animal models ]
To demonstrate the role of platelets in in vivo thrombus occlusion of small diameter electrospun SP material grafts, a 4 mm graft was implanted as a coronary artery bypass graft into a sheep model with various dosing strategies aimed at platelet suppression . The combination of relatively low flow rates (typically <120 mL / min), curved implant pathways, and small diameters are expected to represent the worst-case scenario for synthetic implants, thereby making antiplatelet therapy in vivo ineffective. Effectiveness can be evaluated negatively.

  Prior to surgery, animals were dosed with a combination of heparin, Aspirin ™ and Plavix ™. Since heparin is an established inhibitor of the coagulation pathway by thrombin generation, all observed coagulation reactions can be attributed to platelet generation. Aspirin and Plavix both affect secondary platelet activation, which is the ability of activated platelets to activate additional circulating platelets. Plavix is a more powerful drug. Implants were implanted for 4 hours prior to explantation, fixation, and histology and characterization via SEM. As can be seen in FIG. 7, the increased number of platelet suppression treatments significantly reduced thrombus formation on the nonwoven surface of the implant. These results indicate that platelet activation and aggregation are the primary mechanisms of thrombus formation in vivo.

[ Long-term thrombotic response of small diameter implants of SP electrospun material in large animal models ]
Small diameter implants, including 6 and 7 mm implants of SP electrospun material, are implanted as carotid inclusions in a sheep model (n = 4 and n = 2, respectively) to demonstrate the long term thrombogenic response of the small diameter implant. Implants were obtained by angiography and ultrasonography immediately after transplantation, and then on days 0, 7, 14, 21, 21 and 28, and then monthly. The patency was evaluated. The proximal, distal, and middle portions of the implant were evaluated for changes in lumen diameter during this time. Half of the test animals were sacrificed at 6 months, explants were explanted for gross histological characterization, and the remaining animals were scheduled to be sacrificed and explanted at 12 months.

  Animals were dosed twice daily for 90 days starting at the time of surgery with 0.4 mL of Lovenox® enoxaparin ™ (low molecular weight heparin) and 125 mg once daily until sacrifice. Aspirin ™ was dosed.

  As seen in FIG. 8, angiography showed good patency of the graft before explant at 6 months. FIG. 9 shows the diameter of the distal anastomosis (where thrombotic occlusions are most likely to occur) for which data was taken during the course of the study.

[ Method for producing supramolecular polymer ]
In one exemplary embodiment, the supramolecular polymer can be made using one of the recipes described in U.S. Provisional Application No. 62/611431, filed December 28, 2017, The U.S. patent application is a priority application filed by the present application, the entire contents of which are hereby incorporated by reference.

  According to these recipes, supramolecular compounds are defined as hard blocks covalently bonded to soft blocks. The hard block is based on the UPy part. The soft block is the skeleton of the supramolecular compound. Polycarbonate (PC) was used because it showed a surprisingly advantageous effect on the intent and purpose of the present invention, especially as compared to polycaprolactone.

  The ratio of soft blocks to hard blocks affects material properties. Here, it will be described that the ratio of the constituent components in the hard block section has a great effect on characteristics such as durability. Here, a specific combination of the ratio in the hard block and the length of the polymer used to form the soft block that improves the mechanical properties (durability) is described. The ratio (R) between the 2-ureido-4 [1H] -pyrimidinone compound (UPy compound) and the chain extension in the hard block is such that the chain extension is 1.5 to 3 with respect to the UPy compound.

[PCL polymer-XP1]
Telechelic hydroxy-terminated polycaprolactone with a molecular weight of 800 g / mol (30.0 g, 37.5 mmol, dried under vacuum), 1,6-hexanediol (4.4 g, 37 mmol), and UPy-monomer (6.3 g, 37 mmol) ) Was dissolved in dry DMSO (105 mL) at 80 ° C. To this reaction mixture was added hexamethylene diisocyanate (18.8 g, 111.5 mmol) with stirring, followed by one drop of tin dioctoate. The reaction mixture was stirred at 80 C overnight. The next day, the reaction mixture was cooled to 25 ° C. and the viscosity was reduced by adding additional DMSO to precipitate the mixture in water. The polymer was collected as a white elastic solid, redissolved in chloroform / methanol (7/3 v / v) and reprecipitated with excess methanol. This resulted in a transparent elastic solid after drying under vacuum at 50 ° C. SEC (THF, PS-standard): Mn = 13 kg / mol, D = 1.6. See also WO 2014/185779 (Patent Document 2).

[ PC polymer ]
Polymers made of polycarbonate with a molecular weight of 500-3000 g / ml were synthesized in a manner similar to XP1. Changes were made depending on the length of the polycarbonate and the desired ratio between the components. The molar ratio can be expressed as: A (polycarbonate) is fixed at 1. B (chain extension) is varied between 0-3, D (Upy) is varied between 0.3-2, and C is 0.8-1 of the total molar amount of A, B and D. .2 always equal. The molar ratio B / D is denoted by R. Table 1 provides a list of examples (not all inclusive) of supramolecular polymers obtained according to the above instructions.

Table 1 List of materials

  For example, a feature that can affect durability is the alignment of the fibers in the scaffold. The preferred fiber alignment is in the case of a tubular implant, circumferentially around the virtual axis of the implant, the axis of which is the direction of blood flow. FIG. 11 clearly shows that the fatigue resistance can be increased by the alignment. The alignment, defined as the linear elastic stiffness ratio between the preferred fiber direction and a line perpendicular to the preferred fiber direction, varied up to 8: 1. FIG. 11 is based on a comparison of alignment in electrospun supramolecular polymer heart valves, but it is believed that the same principles apply to cardiovascular grafts.

[ Supplementary information ]
[ 1. Range (mainly durability) ]
-The molar ratio R changed in the range of 0-3. Enhanced / optimal fatigue resistance was obtained at molar ratios above 1.5.
-The length of the PC varied from 500 to 3000 g / mol. When the PC length was 1000, enhanced / best fatigue resistance was obtained.
-The mass ratio of the chain extension changed from 0 to 15. Enhanced / best fatigue resistance was obtained at high HD ratios (> 9 w%).

[ 2. Scaffold structure ]
[ Thickness ] can vary between a few μm and mm, but the preferred thickness is 200-800 μm, more preferably 250-550 μm (an average of 300-500 μm gives good results).
[ Fiber diameter ] can be obtained in a wide range of 1 μm to 20 μm. Preferably, it is carried out in the range of 3 to 15 μm, more preferably in the range of 4 to 10 μm.
[ Fiber Alignment ] is another parameter that enhances durability, especially when electrospinning is not guided, and has a random distribution of 1: 2 (circumferential: axial) organization (axial stiffness) Means twice the circumferential stiffness). The fibers can be arranged in a ratio of infinity: 1-1: 2. In order to greatly improve the durability, it is desirable to carry out at a ratio of 2: 1 to 8: 1.
-[Pore size ]: The matrix material contains pores having a diameter of 1 to 300 µm, preferably 5 to 100 µm.
[ Porosity ]: The matrix material constitutes a fiber network, and the porosity is 50% to 80%.

[ Method for preparing cardiovascular graft ]
In one exemplary embodiment for making a cardiovascular graft, a supramolecular polymer (SP) material obtained, for example, from one of the following recipes is added to a solvent mixture of chloroform and hexafluoroisopropanol at 11.5% by weight. Dissolve to a concentration of This solution is supplied via syringe pump to a blunt-ended stainless steel needle maintained at a voltage of 5-10 kV to produce an electrostatically driven whip jet. The jet is attracted to a cylindrical collector charged to a negative voltage of 1-4 kV, forming a very porous fibrous nonwoven coating. After depositing a 0.5 mm thick electrospun polymer material, removal from the collector device is accomplished by separation with a soft-tipped spatula, resulting in a 0.5 mm wall thickness electrospun tubular implant.

[ Conclusion ]
The data described herein demonstrate the unexpected effects of the cardiovascular grafts of the present invention on platelet activation, adhesion and diffusion. A quantifiable reduction in thrombus formation due to platelet development in cardiovascular grafts has been demonstrated when compared to known biocompatible synthetic polymers (eg, FIG. 4: 27% with electrospun SP material). Porosity reduction, PTFE porosity reduction of 59%). Furthermore, a previously unknown and unexpected dependence on the specific cell adhesion protein glycoprotein IIb / IIIa has been shown. This unexpected interaction is assumed to be based on the result of the surface charge of the electrospun fibers of SP. This dependence of platelet adhesion on specific glycoproteins allows for a single chemotherapeutic agent to contrast with known biocompatible synthetic polymers such as PTFE that require more extensive inhibition of cell adhesion molecules. It is possible to strongly influence thrombosis due to the generation of platelets. It is proposed to conduct further investigations on the incorporation or surface absorption of such chemotherapeutic agents by electrospun fibers of SP material to provide site-specific and very effective platelet inhibition.

Claims (17)

A cardiovascular graft for reducing a thrombus formation effect,
A tubular structure with an inner wall made of a fibrous network of supramolecular compounds having a hard block covalently bonded to a soft block,
The hard block comprises a 2-ureido-4 [1H] -pyrimidinone (UPy) compound,
The fibrous network is a bioabsorbable electrospun nonwoven fiber network having fibers having an average fiber diameter of 1 to 10 μm,
The cardiovascular graft, wherein the tubular structure has an inner diameter of 2 to 8 mm and a wall thickness of 200 to 900 μm. The cardiovascular graft according to claim 1, wherein
Said inner wall has a thickness of at least 20 μm,
The cardiovascular graft according to claim 1, wherein the inner wall has pores, and the pores have an average pore diameter of 5 to 10 m. The cardiovascular graft according to claim 1, wherein
A cardiovascular graft, wherein the inner wall has pores, the average porosity of the inner wall is 50 to 80%, and the average pore diameter of the pores is 5 to 8 μm. The cardiovascular graft according to claim 1, wherein
A cardiovascular graft, wherein the inner diameter of the tubular structure is 3 to 6 mm, and the wall thickness of the tubular structure is 200 to 800 μm. The cardiovascular graft according to claim 1, wherein
The inner diameter of the tubular structure is 4 to 8 mm, and the wall thickness of the tubular structure is 300 to 900 μm. The cardiovascular graft according to claim 1, wherein
A cardiovascular graft, wherein the inner diameter of the tubular structure is 5 mm or less. The cardiovascular graft according to claim 1, wherein
A cardiovascular graft, wherein the fibers have an average fiber diameter of 4 to 8 μm. The cardiovascular graft according to claim 1, wherein
A cardiovascular graft, wherein the fibers have an average fiber diameter of 4 to 6 μm. The cardiovascular graft according to claim 1, wherein
The soft block may be a biodegradable polyester, polyurethane, polycarbonate, poly (ortho) ester, polyphosphoester, polyanhydride, polyphosphazene, polyhydroxyalkanoate, polyvinyl alcohol, polypropylene fumarate, or any combination thereof. A cardiovascular graft, comprising: The cardiovascular graft according to claim 1, wherein
The cardiovascular graft according to claim 1, wherein the soft block has a molecular weight ranging from 500 to 3000 Da. The cardiovascular graft according to claim 1, wherein
A cardiovascular graft, wherein the rigid block comprises a chain extension in the range of 1 to 5, more preferably 1.5 to 3, relative to the UPy compound. The cardiovascular graft according to claim 1, wherein
The inner wall is hydrophobic, and a water contact angle of the inner wall is 110 to 140 degrees. The cardiovascular graft according to claim 1, wherein
A cardiovascular graft, which is a coronary artery bypass graft. The cardiovascular graft according to claim 1, wherein
A cardiovascular graft, which is an arteriovenous graft for dialysis access. The cardiovascular graft according to claim 1, wherein
A cardiovascular graft, wherein the tubular structure has an outer wall reinforced with a braided structure, a polymer strand, a compound, or a combination thereof to provide resistance to preventing the cardiovascular graft from collapsing. The cardiovascular graft according to claim 1, wherein
A cardiovascular graft, further comprising an αIIbβ3 inhibitor. A method for transplanting a cardiovascular graft according to any one of claims 1 to 16,
The method, wherein the transplantation of the cardiovascular graft is performed in combination with administration of an αIIbβ3 inhibitor.